Alcohol abuse is a leading cause of morbidity and mortality worldwide. In the US, 18 million Americans abuse alcohol, with alcoholic liver disease affecting over 10 million people. Alcohol abuse's deleterious effects on the liver leads to pathologically distinct entities. Chronic conditions include steatosis, steatohepatitis, fibrosis ad cirrhosis; patients can develop acute alcoholic hepatitis (AH) at any time in the progression of disease. Disease progression only occurs in a sub-set of heavy drinkers, suggesting a role for genetic and environmental risk factors. There is a pressing clinical need to develop improved therapies for patients with AH, as the current strategy of glucocorticoid (GC) treatment is only effective in a sub-set of patients. Development of novel therapeutic strategies for the treatment of AH requires 1) identification and validation of new drug targets and therapeutic strategies, 2) development of rationally designed and innovative biomarkers that will improve our ability to diagnose AH and rapidly determine the efficacy of treatment strategies and 3) understanding the genetic contributions to both the severity of ASH and sensitivity to therapeutic intervention. In the Cleveland Clinic Translational Component of our U01 application for Novel therapies for alcoholic hepatitis, we will leverage the considerable expertise of basic and clinical investigators to take a three-armed approach to developing improved therapeutic strategies for the treatment of AH. First, we propose translational studies to develop innovative non-invasive biomarkers based on a) breath gas analysis for exhaled volatile organic compounds that are reflective of both intestinal health and liver function and b) urinary analysis of sensitive biomarkers of kidney function which would allow for early diagnosis and treatment of kidney failure in patients with AH. Second, we will carry out pharmacogenomic analyses and bioinformatics to develop genetic signatures that predict sensitivity of patients to individual and/or combined therapies investigated in the Clinical Component of this U01 application. These data will help clinicians to optimize and individualize treatment protocols, as well as identify new therapeutic targets. Lastly, we will develop two lead therapeutics for treating patients with AH in a pre-clinical mouse model: a) regulation of complement activation to decrease inflammation and protect hepatocytes from cell death and b) treatment with tri-butyrate as a colonic fuel source to improve gut integrity. Advances in each of these aims will be accelerated via interactions with the other Translational and Clinical U01 proposals, leading to the development of novel therapeutics for the treatment of patients with both moderate and severe AH. PUBLIC HEALTH RELEVANCE: Alcohol abuse is a leading cause of morbidity and mortality worldwide. In the US, 18 million Americans abuse alcohol, with alcoholic liver disease affecting over 10 million people. Alcohol abuse's deleterious effects on the liver leads to pathologically distinct entities: steatosis, steatohepatitis (ASH), fibrosis and cirrhosis. Disease progression ony occurs in a sub-set of heavy drinkers, suggesting a role for genetic and environmental risk factors. There is a pressing clinical need to develop improved therapies for patients with ASH, as the current strategy of glucocorticoid (GC) treatment is only effective in a sub-set of patients The goals of this application are to advance the development of novel therapeutic strategies for the treatment of ASH by 1) identification and validation of new drug targets and therapeutic strategies by making use of pre-clinical mouse models of ASH, 2) development of rationally designed and innovative biomarkers that will improve our ability to diagnose ASH and rapidly determine the efficacy of treatment strategies and 3) understanding the genetic contributions to both the severity of ASH and sensitivity to therapeutic intervention.